Phase 1b study of GAS6/AXL inhibitor (AVB-500) in recurrent, platinum-resistant ovarian carcinoma.

person Katherine Cynthia Fuh Washington University in St. Louis, St. Louis, MO info_outline Katherine Cynthia Fuh, Michael A. Bookman, Robert L. Coleman, Thomas J Herzog, Premal H. Thaker, Joyce F. Liu, Michelle W. Lane, Reshma A. Rangwala, Gail McIntyre, Bradley J. Monk, Kathleen N. Moore

Authors person Katherine Cynthia Fuh Washington University in St. Louis, St. Louis, MO info_outline Katherine Cynthia Fuh, Michael A. Bookman, Robert L. Coleman, Thomas J Herzog, Premal H. Thaker, Joyce F. Liu, Michelle W. Lane, Reshma A. Rangwala, Gail McIntyre, Bradley J. Monk, Kathleen N. Moore Organizations Washington University in St. Louis, St. Louis, MO, University of Arizona, Tucson, AZ, Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, Division of Gynecologic Oncology, The University of Cincinnati Cancer Institute, Cincinnati, OH, Department of Gynecologic Oncology, Washington University School of Medicine, St. Louis, MO, Dana-Farber Cancer Institute, Boston, MA, Aravive, Inc, Houston, TX, Merck & Co., Inc., North Wales, PA, Aravive, Inc., Houston, TX, Arizona Oncology (US Oncology Network), University of Arizona College of Medicine, Phoenix, AZ, Stephenson Cancer Center, Oklahoma City, OK Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Aravive, Inc Background: AVB-500 is a first-in-class Fc fusion protein that binds the GAS6 ligand thereby inhibiting AXL signaling. Both GAS6 and AXL are highly expressed in high-grade serous ovarian cancer (HSGOC). This study evaluated safety, tolerability, and preliminary efficacy of AVB-500 in combination with pegylated liposomal doxorubicin (PLD) and paclitaxel (Pac) and determine the recommended Phase 2 dose (RP2D). Methods: Patients were enrolled in escalating dose cohorts of AVB-500 10mg/kg to 20mg/kg q2 weeks in combination with weekly Pac 80mg/m 2 D1, 8, 15 q28 days or PLD 40mg/m 2 D1 q28 days and assess for safety, pharmacokinetics, pharmacodynamics, and response by investigator, via RECIST v1.1. Results: A total of 53 patients with platinum-resistant HGSOC (PROC) were enrolled. A total of 23 patients received Pac + AVB-500 and 30 patients received PLD + AVB-500. Grade 3 or 4 treatment-related adverse events were observed in 4/23 (17%) and 2/30 (7%) PAC and PLD, respectively. No patients discontinued therapy due to an adverse event. Most events were related to known chemotherapy side effects. RP2D was identified as 15mg/kg. Confirmed overall response rate (ORR) with Pac+AVB-500 was 35% (8/23) including 2 CRs and 11% (3/28) in the PLD+AVB-500 subgroup. ORR was 19% (3/16) in patients with platinum free interval (PFI) of < 3 months versus (vs) 23% (8/35) in patients with PFI of 3-6 months. ORR was 11% (2/18) in patients with 1 prior treatment vs 27% (9/33) in patients with 2-3 prior lines of therapy. ORR in patients without prior bevacizumab was 33% (9/27) vs 8% (2/24) in those with prior bevacizumab. Patients treated with Pac combination and whose AVB-500 trough levels were above the minimal efficacious concentration (MEC) of 13.8mg/L achieved the greatest benefit with ORR, median PFS, and median OS of 43% (6/14), 3.9 months, and 17.8 months vs 22% (2/9), 2.8 months, and 8.7 months observed in those whose trough was below the MEC. Among the Pac treated subgroup, the ORR was 47% (13% CR) vs 0% for those with sAXL/GAS6 ratios > 0.773 compared to ratios <0.773. 67% of patients had baseline sAXL/GAS6 > 0.773. Conclusions: AVB-500 is a novel Fc fusion protein that binds the GAS6 ligand and inhibits AXL signaling. AVB-500 was well-tolerated in combination with Pac or PLD. This Ph1b trial suggested a higher ORR in the Pac treated subgroup, with C1D15 trough levels > 13.8mg/L (most consistently achieved at the 15mg/kg dose level). Exploratory analyses suggested that improved ORR may be observed in patients who have not been exposed to bevacizumab. The serum sAXL/GAS6 ratio may be a potential biomarker of pathway activation and identify patients who most benefit from Pac+AVB-500. The ORR in patients with PFI < 3 months or who had > 1 line of prior therapy were similar to those with 3-6 months PFI or ≤1 lines of therapy. Further development of AVB-500 15 mg/kg q2 weeks in combination with Pac is warranted in PROC. Clinical trial information: NCT03639246